Process for producing optically active tropinonemonocarboxylic acid ester derivative

ABSTRACT

An optically active tropinonemonocarboxylic acid ester derivative useful as an intermediate for synthesis of optically active tropane derivatives was obtained by reacting succindialdehyde with an organic amine and acetonedicarboxylic acid ester to obtain a tropinonedicarboxylic acid ester derivative, and then subjecting this derivative to enzyme-catalyzed asymmetric dealkoxy-carbonylation. Since anhydroecgonine methyl ester derived from the optically active tropinone-monocarboxylic acid ester derivative by reduction and dehydration had the same direction of optical rotation as in the case of anhydroecgonine methyl ester obtained from natural cocaine, it was proved that the obtained optically active tropinonemonocarboxylic acid ester derivative had the same absolute configuration as that of natural cocaine. The yield of the optically active tropinonemonocarboxylic acid ester derivative from the asymmetric dealkoxycarbonylation was 30 to 50 mol %, and its optical purity was 70 to 97% ee. In addition, it was found that a crystalline optically active anhydroecgonine carboxylic acid ester derivative can be obtained by reducing and then dehydrating the optically active tropinonemonocarboxylic acid ester derivative and that its optical purity can easily be increased by recrystallization.

TECHNICAL FIELD

[0001] This invention relates to a process for producing an opticallyactive tropinonemonocarboxylic acid ester derivative which is anintermediate for synthesis of alkaloids having the same optically activetropane skeleton as the skeleton of cocaine having affinity for dopaminereceptors or dopamine transporters as a pharmacological action.

BACKGROUND ART

[0002] In recent years, as the span of human life extends, patients withpsychoneurotic diseases such as Parkinson's disease, Alzheimer'sdisease, etc. increase rapidly with a growth of the aged population, andthe investigation of the cause of these psychoneurotic diseases and theestablishment of therapeutic methods for them are accelerated atpresent. Parkinson's disease is chronic and progressive and their mainsymptoms are tremor, myoatrophy, akinesia, and impediment in posturemaintenance. This diseases is caused by the loss of the balance betweendopaminergic nervous system and cholinergic nervous system which isattributable to a marked decrease in the dopamine content of the striatabody and substantia nigra of extrapyramidal motor system.

[0003] Therefore, in order to treat, for example, Parkinson's disease,it is necessary to supply the dopamine deficiency or control thecholinergic nervous system in an excited state.

[0004] On the other hand, cocaine is an alkaloid contained in leaves of,for example, Erythroxylon coca of South America growth, and wasclinically used as a local anesthetic in 1877 for the first time byKoller. Cocaine has recently been found to have affinity for dopaminereceptors or dopamine transporters, and it is being revealed thatcocaine derivatives are useful as various tracer ligands. The basicstructure of cocaine is its tropane skeleton. When cocaine is used as astarting material for a cocaine derivative, an optically active tropaneskeleton having the same absolute configuration as that of the skeletonof natural (−)-cocaine can easily be derived as shown in the followingreaction scheme A (A. P. Kozikowski, J. Med. Chem. 1995, 38, 3086):

[0005] As derivatives thus synthesized by using (−)-cocaine as astarting material, there are, for example,2β-carbomethoxy-3β-(4-iodophenyl)-tropane (β-CIT; USP 5310912) and itsderivative2β-carbomethoxy-3β-(4-iodophenyl)-8-(3-fluoropropyl)-nortropane(β-CIT-FP; WO 96/39198) which have affinity for dopamine transportersand are noted as diagnotic drugs for Parkinson's disease;(−)-ferruginine, an agonist for nicotine-like acetylcholine receptors;and (+)-knightinol.

[0006] Cocaine, however, is designated as a narcotic because of problemssuch as drug dependence, and there are various difficulties in obtainingand handling cocaine. Therefore, it is desirable to develop aneconomical and easy synthetic process of a cocaine analogue.

[0007] Attempts have been made to synthesize cocaine analogues sinceearly times. Robinson et al. synthesized tropinone by condensingsuccindialdehyde with methyl amine and ethyl acetonedicarboxylate(Robinson R., J. Chem. Soc. 1917, 762-768). In 1991, anhydroecgoninemethyl ester was synthesized from vinyldiazomethane and a pyrrolederivative by using a rhodium catalyst (Hum M. L. Davies et al., J. Org.Chem. 1991, 56, 5696-5700, Japanese Patent Application Kohyo No.7-504665). The cocaine analogues synthesized by these processes are notoptically active. As the synthesis of an optically active cocaineanalogue, there is a case where (R)-allococaine or (R)-allopseudococainewas synthesized by saponifying cocaine or using as an intermediate,(R)-pseudoecgonine methyl ester obtained by optical resolution of(RS)-2-carbomethoxy-3-tropinone (F. I. Carroll et al., J. Med. Chem.1991, 34, 883-886).

[0008] An example of enantio-selective asymmetric reaction withoutoptical resolution is the syntheses of an optically activetropinonemonocarboxylic acid ester and anhydroecgonine methyl ester bythe asymmetric synthetic reaction of tropinone with chiral lithium amide(Majewski M., J. Org. Chem. 1995, 60, 5825-5830). The thus obtainedanhydroecgonine methyl ester, however, has an absolute configurationdifferent from that of anhydro-ecgonine methyl ester derived fromnatural (−)-cocaine.

DISCLOSURE OF THE INVENTION

[0009] In view of such conditions, the present invention is intended toprovide a process for producing an optically activetropinonemonocarboxylic acid ester derivative useful as an intermediatefor synthesizing an optically active tropane derivative without usingcocaine as a starting material.

[0010] The present invention relates to a process for producing anoptically active tropinonemonocarboxylic acid ester derivative whichcomprises subjecting a tropinonedicarboxylic acid ester derivativerepresented by the following formula (1):

[0011] wherein R′ is an alkyl group, an aralkyl group or anamino-protecting group selected from lower aliphatic acyl groups,aromatic acyl groups, lower alkoxycarbonyl groups, aralkyloxycarbonylgroups, aryloxycarbonyl groups and tri-lower-alkylsilyl groups, and R isan alkyl group or an aralkyl group, to asymmetric dealkoxycarbonylationin the presence of an enzyme to obtain an optically activetropinonemonocarboxylic acid ester derivative represented by thefollowing formula (2):

[0012] wherein R and R′ are as defined above.

[0013] The present invention also relates to a process for producing anoptically active tropinonemonocarboxylic acid ester derivative whichcomprises reacting succindi-aldehyde represented by the followingformula (3):

[0014] with an organic amine represented by the following formula (4):

R″—NH₂  (4)

[0015] wherein R″ is an alkyl group or an aralkyl group, and anacetonedicarboxylic acid ester represented by the following formula (5):

[0016] wherein R is an alkyl group or an aralkyl group; if necessary,converting the substituent derived from the substituent R″ of theorganic amine of the formula (4) to an amino-protecting group; therebyobtaining a tropinonedicarboxylic acid ester derivative represented bythe following formula (1):

[0017] wherein R′ is an alkyl group, an aralkyl group or anamino-protecting group selected from lower aliphatic acyl groups,aromatic acyl groups, lower alkoxycarbonyl groups, aralkyloxycarbonylgroups, aryloxycarbonyl groups and tri-lower-alkylsilyl groups, and R isan alkyl group or an aralkyl group; and then subjecting thetropinonedicarboxylic acid ester derivative to asymmetricdealkoxycarbonylation in the presence of an enzyme to obtain anoptically active tropinonemonocarboxylic acid ester derivativerepresented by the following formula (2):

[0018] wherein R and R′ are as defined above.

[0019] The present invention further relates to a process for producingan optically active anhydro-ecgonine carboxylic acid ester derivativewhich comprises converting the substituent R′ and/or substituent R ofthe optically active tropinonemonocarboxylic acid ester derivative ofthe above formula (2) to another substitu-ent or other substituents ifnecessary, reducing the oxo group at the 3-position of this derivative,and then dehydrating the resulting compound to obtain an opticallyactive anhydroecgonine carboxylic acid ester derivative represented bythe following formula (6):

[0020] wherein R and R′ are as defined above.

BEST MODE FOR CARRYING OUT THE INVENTION

[0021] The optically active tropinonemonocarboxylic acid esterderivative obtained by the production process of the present inventionis useful as an intermediate for synthesizing a cocaine analogue withoutusing cocaine as a starting material, said cocaine analogue having atropane skeleton, the basic ring structure of cocaine, and having thesame optical activity as that of a cocaine analogue derived from natural(−)-cocaine.

[0022] The tropinonedicarboxylic acid ester derivative of the aboveformula (1), the starting material in the production process of thepresent invention, may be synthesized by the process shown in thefollowing reaction scheme B:

[0023] As shown in the reaction scheme B, the tropinonedicarboxylic acidester derivative of the formula (1) is synthesized by reactingsuccindialdehyde of the formula (3) with an organic amine of the formula(4) and an acetonedicarboxylic acid ester of the formula (5) and, ifnecessary, converting the substituent derived from the substituent R″ ofthe organic amine of the formula (4) to an amino-protecting group.

[0024] Succindialdehyde of the formula (3) is a well-known compound andis obtained, for example, by hydrolyzing 2,5-dimethoxytetrahydrofuran.

[0025] The organic amine of the formula (4) and the acetonedicarboxylicacid ester of the formula (5) are also well-known compounds and aresynthesized by per se well-known processes. Each of the substituent R″of the organic amine of the formula (4) and the substituent R of theacetonedicarboxylic acid ester of the formula (5) is an alkyl group oran aralkyl group. Specific examples of the alkyl group are alkyl groupsof 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group,isopropyl group, butyl group, s-butyl group, t-butyl group, pentylgroup, isopentyl group, neopentyl group, t-pentyl group, hexyl group,etc. Specific examples of the aralkyl group are aralkyl groups of 7 to10 carbon atoms, such as benzyl group, phenethyl group, phenylpropylgroup, phenylbutyl group, etc.

[0026] The reaction of succindialdehyde of the formula (3) with theorganic amine of the formula (4) and the acetonedicarboxylic acid esterof the formula (5) is per se well known. For example, when each of thesubstitu-ents R and R″ is a methyl group (Me), a methanolic solutioncontaining dimethyl 1,3-acetonedicarboxylate is added to a methanolsolution of succindialdehyde in an ice bath under a nitrogen atmosphere,a methanolic solution containing methylamine is added dropwise theretoin an ice bath and stirred overnight, and the solvent is distilled offto obtain dimethyl8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1a: R′=Meand R=Me in the formula (1)) in a yield of 70-90 mol %.

[0027] The thus obtained tropinonedicarboxylic acid ester derivative maybe subjected as it is to the asymmetric dealkoxycarbonylation explainedhereinafter. If necessary, the alkyl or aralkyl group as the substituentR′ of the amino group at the 8-position derived from the substituent R″of the organic amine of the formula (4) may be converted to anamino-protecting group. The amino-protecting group includes loweraliphatic acyl groups, aromatic acyl groups, lower alkoxycarbonylgroups, aralkyloxycarbonyl groups, aryloxycarbonyl groups andtri-lower-alkylsilyl groups, etc. As the lower aliphatic acyl groups,there may be exemplified lower aliphatic acyl groups of 2 to 7 carbonatoms, such as acetyl group, propanoyl group, butanoyl group, pentanoylgroup, hexanoyl group, etc. As the aromatic acyl groups, there may beexemplified aromatic acyl groups of 7 to 11 carbon atoms, such asbenzoyl group, naphthanoyl group, etc. As the lower alkoxy-carbonylgroups, there may be exemplified lower alkoxycarbonyl groups of 2 to 7carbon atoms, such as methoxycarbonyl group, ethoxycarbonyl group,butoxy-carbonyl group, t-butoxycarbonyl group, etc. As thearalkyloxycarbonyl groups, there may be exemplified aralkyloxycarbonylgroups of 8 or 9 carbon atoms, such as benzyloxycarbonyl group,methoxybenzyloxycarbonyl group, etc. As the aryloxycarbonyl groups,there may be exemplified aryloxycarbonyl groups of 7 to 11 carbon atoms,such as phenoxycarbonyl group, naphthoxycarbonyl group, etc. As thetri-lower-alkylsilyl groups, there may be exemplifiedtri(C₁-C₆)alkylsilyl groups such as trimethylsilyl group, triethylsilylgroup, tributylsilyl group, etc.

[0028] The conversion to any of these amino-protecting groups is a perse well-known reaction.

[0029] A desired optically active tropinonemonocarboxylic acid esterderivative of the formula (2) is obtained by subjecting the thusobtained tropinonedi-carboxylic acid ester derivative of the formula (1)to asymmetric dealkoxycarbonylation using an enzyme, as shown in thefollowing reaction scheme C:

[0030] In this case, the optically active tropinone-monocarboxylic acidester derivative of the formula (2) obtained by enzyme-catalyzedasymmetric dealkoxycarbonylation of the ester group at the 2- or4-position of the tropinonedicarboxylic acid ester derivative of theformula (1) is effectively used as an intermediate for synthesis ofvarious cocaine analogues.

[0031] The yield of the optically active tropinone-monocarboxylic acidester derivative of the formula (2) from the asymmetricdealkoxycarbonylation of the tropinonedicarboxylic acid ester derivativeof the formula (1) and its optical purity are affected by the kinds ofthe substituent R′ of the amino group at the 8-position, the substituentR of the ester group at the 2- or 4-position and the enzyme used. Inparticular, the kinds of the substituent of the ester group and theenzyme used have a great influence.

[0032] As the enzyme used in the present invention, there may beexemplified liver esterases such as porcine liver esterase (PLE), rabbitliver esterase, horse liver esterase, etc.; and baker's yeast (B.Y.). Inparticular, porcine liver esterase (PLE) and baker's yeast (B.Y.) aresuitably used.

[0033] A preferable combination of the substituent R′ of the amino groupat the 8-position and the substituent R of the ester group at the 2- or4-position of the tropinonedicarboxylic acid ester derivative of theformula (1) is a combination wherein R is an alkyl group of 1 to 6carbon atoms and R′ is an aralkyl group, a lower aliphatic acyl group,an aromatic acyl group, an aryloxycarbonyl group or atri-lower-alkylsilyl group; a combination wherein R is an alkyl group of2 to 6 carbon atoms and R′ is an aralkyloxycarbonyl group; or acombination wherein each of R and R′ is an aralkyl group. Morespecifically, preferable is a combination wherein R is an alkyl group of1 to 6 carbon atoms selected from methyl group, ethyl group, propylgroup, isopropyl group, butyl group, isobutyl group, s-butyl group,t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentylgroup and hexyl group, and R′ is an aralkyl group of 7 to 10 carbonatoms selected from benzyl group, phenethyl group, phenylpropyl groupand phenylbutyl group; a combination wherein R is an alkyl group of 2 to6 carbon atoms selected from ethyl group, propyl group, isopropyl group,butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group,isopentyl group, neopentyl group, t-pentyl group and hexyl group, and R′is an aralkyloxycarbonyl group of 8 or 9 carbon atoms selected frombenzyloxycarbonyl group and methoxybenzyl-oxycarbonyl group; or acombination wherein each of R and R′ is an aralkyl group of 7 to 10carbon atoms selected from benzyl group, phenethyl group, phenylpropylgroup and phenylbutyl group.

[0034] Preferable examples of the tropinonedicarboxylic acid esterderivative of the formula (1) which have any of these combinations arethe following compounds:

[0035] dimethyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate (1b: R′=Bnand R=Me in the formula (1)),

[0036] diethyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate (1c: R′=Bnand R=Et in the formula (1)),

[0037] diisopropyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate (1d: R′=Bnand R=i−Pr in the formula (1)),

[0038] dibutyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate (1e: R′=Bnand R=n−Bu in the formula (1)),

[0039] dibenzyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate (1f: R′=Bnand R=Bn in the formula (1)), and

[0040] diethyl8-benzyloxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate(1g: R′=Z and R=Et in the formula (1)).

[0041] The asymmetric dealkoxycarbonylation is carried out at pH 7-9 andat a temperature of approximately 10-40° C. As a buffer solution, thereare used phosphate buffer solutions, toluene-phosphate buffer solutions,Tris buffer solutions, HEPES buffer solutions, etc. The amount of theenzyme used is varied depending on the kind of the enzyme. For example,the amount of PLE is 500-5,000 units/mmol substrate, and the amount ofB.Y. is 1-5 g/mmol substrate.

[0042] The optically active tropinonemonocarboxylic acid esterderivative of the formula (2) is obtained by the asymmetricdealkoxycarbonylation. When the compounds described above as preferableexamples of the tropinone-dicarboxylic acid ester derivative of theformula (1) are used, the following corresponding compounds of theformula (2) are obtained:

[0043] methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2b:R′=Bn and R=Me in the formula (2)),

[0044] ethyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2c:R′=Bn and R=Et in the formula (2)),

[0045] isopropyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2d:R′=Bn and R=i−Pr in the formula (2)),

[0046] butyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2e:R′=Bn and R=n−Bu in the formula (2)),

[0047] benzyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2f:R′=Bn and R=Bn in the formula (2)), and

[0048] ethyl(1R,5S)-8-benzyloxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate((−)-2g: R′=Z and R=Et in the formula (2)).

[0049] The optically active tropinonemonocarboxylic acid esterderivative obtained according to the present invention is a mixture ofthree kinds of isomers, i.e., enol form and two keto forms as shown inthe following reaction scheme D. This fact can be confirmed by NMR dataof the derivative.

[0050] Therefore, the optical purity of the optically activetropinonemonocarboxylic acid ester derivative obtained according to thepresent invention was measured by converting said derivative to an α,β-unsaturated ester compound, a single compound by reduction anddehydration as shown in the following reaction scheme E, and thensubjecting this ester compound to HPLC using a chiral column:

[0051] Specifically, for example, each of the above-exemplifiedcompounds (−)-2c, (−)-2d, (−)-2e and (−)-2f, i.e., optically activetropinonemonocarboxylic acid ester derivatives obtained according to thepresent invention is converted to the above-exemplified compound (−)-2b,a methyl ester compound by transesterification, which is then convertedto the α, β-unsaturated ester compound A by reduction and dehydration,and the compound A is subjected to HPLC using a chiral column (eluent:hexane:2-propanol=100:1), whereby the optical purity was measured. Theoptical purity of the above-exemplified compound (−)-2g having abenzyloxycarbonyl group as a protecting group for the amino group may bemeasured by removing the benzyloxycarbonyl group with trifluoroaceticacid (TFA), benzylating the resulting compound into theabove-exemplified compound (−)-2c, and then converting the compound(−)-2c to the α, β-unsaturated ester compound A in the manner shown inthe reaction scheme E.

[0052] α, β-Unsaturated ester compound A in dl-form used as a referencestandard compound was synthesized by hydrolyzing dimethyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate (1b: R′=Bnand R=Me in the formula (1)) with LiOH, decarboxylating the hydrolysateinto tropinonemonoester with 2N-HCl, and reducing this compound withNaBH₄, followed by dehydration.

[0053] As to the absolute configuration, as shown in the followingreaction scheme F, each of the above-exemplified compounds (−)-2c,(−)-2d, (−)-2e, (−)-2f and (−)-2g, i.e., the optically activetropinonemonocarboxylic acid ester derivatives obtained according to thepresent invention, is converted to methyl8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((+)-B), and thiscompound is reduced and then dehydrated to obtain anhydroecgonine methylester ((−)-C). On the other hand, as shown in the following reactionscheme G, natural (−)-cocaine was converted to anhydroecgonine methylester. When the anhydroecgonine methyl ester obtained from each of theabove-exemplified compounds was compared with that obtained from natural(−) -cocaine, their directions of optical rotation were the same (−) inthe case of all the above-exemplified compounds. It was confirmed bythis fact that the absolute configuration of the optically activetropinonemonocarboxylic acid ester derivative obtained by the enzymereaction according to the present invention is identical to that of(−)-cocaine.

[0054] The thus obtained optically active tropinonemonocarboxylic acidester derivative according to the present invention may be converted toan optically active anhydroecgonine carboxylic acid ester derivativerepresented by the following formula (6):

[0055] wherein R and R′ are as defined above, by converting thesubstituent R′ and/or the substituent R to another substituent or othersubstituents if necessary, and then reducing the oxo group at the3-position, followed by dehydration. Such an optically activeanhydroecgonine carboxylic acid ester derivative is useful as anintermediate for synthesis of drugs such as2β-carbomethoxy-3β-iodophenyl)tropane (β-CIT) and its derivativesincluding β-CIT-FP and tropane alkaloids such as (−)-ferruginine.

[0056] (+)-Ferruginine is an alkaloid isolated from Darlingianaferruginea and D. darlingiana, and its enantiomer (−)-ferruginine isknown as an agonist for nicotine-like acetylcholine receptors. The(+)-form and (−)-form of ferruginine have been synthesized fromL-glutamic acid (H. Rapoport et al., J. Org. Chem. 1996, 61, 314).

[0057] For example, using butyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2e:R′=Bn and R=n−Bu in the formula (2)), an optically activetropinonemonocarboxylic acid ester derivative obtained according to thepresent invention, (−)-ferruginine may be synthesized as shown in thefollowing reaction scheme H.

[0058] At first, butyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2e)is converted to methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2b:R′=Bn and R=Me in the formula (2)) by transesterification, and then thebenzyl group as a protecting group for the amino group is removed bycatalytic reduction and a t-butoxycarbonyl (Boc) group is introduced.The resulting keto-ester, methyl(1R,5S)-8-t-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate((−)-2h: R′=Boc and R=Me in the formula (2)) is reduced with NaBH₄ andthen dehydrated to obtain methyl (1R,5S)-8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate ((−)-6a:R′=Boc and R=Me in the formula (6)), an optically active anhydroecgoninecarboxylic acid ester derivative. The methyl ester group and Boc groupof the optically active anhydroecgonine carboxylic acid ester derivativeobtained are replaced by an acetyl group and a methyl group,respectively, by well-known methods to obtain a desired compound(−)-ferruginine.

[0059] Physiological properties such as optical rotation, ¹H-NMR, etc.of the optically active anhydroecgonine carboxylic acid ester derivativeobtained above, i.e., methyl(1R,5S)-8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate((−)-6a), agree with the values described in a reference (H. Rapoport etal., J. Org. Chem. 1996, 61, 314). Thus, the synthesis of(−)-ferruginine has been achieved.

[0060] As shown in the following reaction scheme I, each of the drug 2β-carbomethoxy-3β-(4-iodophenyl)-tropane (β-CIT) and its derivativeβ-CIT-FP may be synthesized from methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2b:R′=Bn and R=Me in the formula (2)), an optically activetropinonemonocarboxylic acid methyl ester obtained according to thepresent invention.

[0061] In detail, the benzyl group of methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2b)is replaced by a methyl group to obtain methyl(1R,5S)-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((+)-2a:R′=Me and R=Me in the formula (2)). Thereafter, the obtained compoundmay be converted to methyl(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate ((−)-6b:R′=Me and R=Me in the formula (6)), optically active anhydroecgoninemethyl ester by reduction with NaBH₄ followed by dehydration. From thisoptically active anhydroecgonine methyl ester, β-CIT or β-CIT-FP may besynthesized according to a well-known process.

[0062] As exemplified above, the optically activetropinonemonocarboxylic acid ester derivative of the formula (2)obtained by the process of the present invention may be converted to anoptically active anhydroecgonine carboxylic acid ester derivative of theformula (6) which is useful as an intermediate for synthesis of drugs,by converting the substituent R′ and/or the substituent R to anothersubstituent or other substituents if necessary, and then reducing theoxo group at the 3-position, followed by dehydration. In this case, theconversion of the substituent R′ and/or the substituent R to anothersubstituent or other substituents may be carried out by a well-knownreaction such as transesterification as is clear from the exampledescribed above. The reduction and dehydration are per se well-knownreactions. For example, the reduction may be carried out with NaBH₄ orPtO₂, and the dehydration may be carried out with trifluoroaceticanhydride (TFAA), POCl₃ or the like.

[0063] The anhydroecgonine carboxylic acid ester derivative obtainedaccording to the present invention is optically active and is veryuseful as an intermediate for synthesis of drugs.

[0064] In general, the optical purity of an optically active substanceused as a drug is very important in imparting a specific pharmacologicaleffect and preventing side effects, etc. Easy production of an opticallyactive tropinonemonocarboxylic acid ester derivative having a highoptical purity has been successfully achieved by carrying out theasymmetric dealkoxycarbonylation of a tropinonedicarboxylic acid esterderivative according to the present invention. In addition, it hasbecome possible to obtain easily an anhydroecgonine ester derivativehaving a very high optical purity by synthesizing an anhydroecgoninecarboxylic acid ester derivative by the use of the optically activetropinonemonocarboxylic acid ester derivative having a high opticalpurity. Moreover, it is possible to synthesize a crystallineanhydroecgonine ester derivative. Furthermore, it has become possible toproduce easily a crystalline anhydroecgonine ester derivative having amuch higher optical purity by purification by recrystallization.

[0065] For example, when as shown in the following reaction scheme J,methyl(1R,5S)-8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate((−)-6a: R′=Boc and R=Me in the formula (6)) was synthesized byconverting the substituent of the amino group of methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2b:R′=Bn and R=Me in the formula (2)) to a Boc group, and reducing theresulting compound, followed by dehydration, colorless needles (mp79-80° C.) were obtained. Thus, it has become very easy to increase theoptical purity by recrystallization. Crystalline methyl(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate ((−)-6b:R′=Me and R=Me in the formula (6)) having a very high optical purity maybe synthesized by replacing the Boc group of the compound (−)-6a by amethyl group.

[0066] The present invention is illustrated in further detail with thefollowing examples, which should not be construed as limiting the scopeof the invention.

[0067] Methods for measuring physical properties of substances obtained,common solvents, etc. are as follows.

[0068] (1) Melting point: Measured by using a micro hot-stage apparatus(Yanagimoto) and a directly heated capillary melting point apparatus(Mitamura Riken Industries, Ltd.).

[0069] (2) ¹H-NMR: Measured with a Varian XL-300 spectrometer. Chemicalshift values are expressed in ppm by using tetramethylsilane (TMS) as aninternal standard.

[0070] (3) Optical rotation: Measured with Horiba Sepa-200.

[0071] (4) Infrared spectrum: Measured with Jasco IR-810 and SHIMADZUFTIR-8300. Frequencies are expressed in cm⁻¹.

[0072] (5) Mass spectrum: Measured with a JEOL JMX-SX102AQQ massspectrometer and a JEOL JMS-GCmate mass spectrometer.

[0073] (6) Elemental analysis: Measured with PERKINELMER Series CHNS/OAnalyzer 2400.

[0074] (7) Silica gel for chromatography: Wakogel C-200 (Wako PureChemical Industries, Ltd.), Silica Gel 60 PF₂₅₄ (Nacalai Tesque, Inc.),Kieselgel 60 Art. 9385 (Merck), TLC-Kieselgel 60 Art. 11695 (Merck),Silica Gel 60 N (Kanto Chemical Co., Inc.) and SIL-60-S75 (YMC CO.,LTD.) were used.

[0075] (8) Silica gel plates for preparative-TLC: Kieselgel 60 F₂₅₄Art.5715 (Merck, 0.25 mm) and Kieselgel 60 F₂₅₄Art. 5744 (Merck, 0.5 mm)were used.

[0076] (9) Preparative-HPLC: JAI LC-908 was used. As columns, JAIGEL-1H,JAIGEL-2H and JAIGEL-SIL S-043-15 were used.

[0077] (10) HPLC for qualitative analysis: Shimadzu LC-10A was used. Asa column, Daicel Chiral Column (CHIRALCEL OD) was used.

[0078] (11) Solvents: As an ether solvent or aromatic solvent used ineach reaction, there was used one which had been made anhydrous bydistilling from sodium benzophenone ketyl at the time of use. Aschloroform, there was used one which had been mede anhydrous bydistilling from CaCl₂, after ten washings with water to remove astabilizer ethanol at the time of use. As other anhydrous solvents,there were used those which had been made anhydrous according to aconventional method.

[0079] (12) The following abbreviations are used in the examplesdescribed below:

[0080] Ac; acetyl group, Bn; benzyl group, Bu; butyl group, Boc:t-butoxycarbonyl group, Z; benzyloxycarbonyl group, DMAP;4-dimethylaminopyridine, Et₃N; triethylamine, MeOH; methanol, THF;tetrahydrofuran, AcOEt; ethyl acetate, PLE; porcine liver esterase, PPL;porcine pancreas lipase, B.Y.; baker's yeast, MS4A; molecular sieve 4A.

EXAMPLE 1

[0081] Synthesis of dimethyl8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1a: R′=Meand R=Me in the formula (1))

[0082] To an aqueous solution (30 ml) of of 2,5-dimethoxytetrahydrofuran(6.48 ml, 50 mmol) was added concentrated hydrochloric acid (6 ml), andthe resulting mixture was stirred at room temperature for 3 hours. Aftercompletion of the reaction, the reaction solution was neutralized withpotassium carbonate and the excess methanol was evapolated under reducedpressure. The residue was extracted by using an Extrelut colomn, acolomn for extraction, with chloroform. The extract was dried over MS4Aand magnesium sulfate, filtered and concentrated in vacuo, whereby acrude product of succindialdehyde was obtained.

[0083] Under a nitrogen atmosphere, to the obtained succindialdehydewere added droupwise a methanol (70 ml) solution of dimethyl1,3-acetonedicarboxylate (7.49 ml, 70 mmol) and a methanol (30 ml)solution of methylamine (7.15 ml, 70 mmol) at 0° C. and the mixture wasstirred overnight. After completion of the reaction, the solvent wasevapolated under reduced pressure and the thus obtained crude productwas purified by a silica gel column chromatography (CHCl₃: MeOH=100:1)to obtain 11.9 g of the title compound dimethyl8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate. The yieldwas 91 mol %.

[0084] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); ¹H-NMR (CDCl₃, 300 MHz): δ 11.9 (s, 0.43H), 11.8(s,0.43H), 4.01-3.47(m, 8H), 3.18(d, J=2.4 Hz, 0.38H), 2.98(d, J=1.2 Hz,0.76H), 2.39(s, 1.29H), 2.30(s, 1.71H), 2.27-1.51(m, 4H); IR (CHCl₃):3689, 1735, 1654, 1622, 1444, 1249, 1244, 1174 cm⁻¹; MS(FAB) m/z356(M⁺+H, 100), HRMS(FAB) C₁₂H₁₈NO⁵ (M⁺+H): Calcd. 256.1185, Found256.1179.

EXAMPLE 2

[0085] Synthesis of dimethyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1b: R′=Bn and R=Me in the formula (1))

[0086] Under a nitrogen atmosphere, a methanol (15 ml) solution ofbenzylamine (5.46 ml, 50 mmol) was added dropwise to a methanol (15 ml)solution of succindialdehyde obtained in the same manner as in Example1, at 0° C. and stirred for 2 hours. Then, a methanol (15 ml) solutionof dimethyl 1,3-acetonedicarboxylate (7.22 ml, 50 mmol) was addeddropwise at 0° C. and the reaction mixture was stirred for an additional19 hours.

[0087] After completion of the reaction, the solvent was evapolatedundder reduced pressure and the thus obtained crude product was purifiedby a silica gel column chromatography (AcOEt:hexane=1:5) to obtain 11.8g of the title compound dimethyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]-octane-2,4-dicarboxylate. The yieldwas 74 mol %.

[0088] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); ¹H-NMR (CDCl₃, 300 MHz): δ 11.9(s, 0.25H), 11.8(s,0.25H), 7.34-7.24(m, 5H), 4.09-3.82(m, 1H), 3.78-3.57(m, 9H), 3.37(s,0.33H), 3.33(s, 0.33H), 3.18(d, J=2.4 Hz, 0.33H), 2.96(d, J=1.5 Hz,0.5H), 2.25-1.49(m, 4H); IR (CHCl₃): 3690, 1738, 1659, 1620, 1603, 1445,1263, 1236 cm⁻¹; MS(FAB) m/z 332(M⁺+H, 100); HRMS(FAB) C₁₈H₂₂NO₅ (M⁺+H):Calcd. 332.1498, Found 332.1493.

EXAMPLE 3

[0089] Synthesis of dimethyl8-benzyloxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate(1h: R′=Me and R=Z in the formula (1))

[0090] To a solution in acetic acid (50 ml) of the dimethyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate obtained inExample 2 was added 10% Pd—C (catalytic amount), and the resultingmixture was stirred for 9 hours under a hydrogen atmosphere at 40° C.After completion of the reaction, the mixture was filtered with Celiteand concentrated in vacuo. The residue was adjusted to pH 8.0-8.5 with asaturated sodium carbonate solution and extracted with chloroform. Theextract was dried over Na₂SO₄, filtered and concentrated in vacuo,whereby a crude product of a debenzylated derivative dimethyl3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate was obtained. To asolution of the obtained debenzylated derivative in chloroform (80 ml)were added benzyloxycarbonyl chloride (1.80 ml, 12.6 mmol) andtriethylamine (1.76 ml, 12.6 mmol), and the resulting mixture wasstirred under a nitrogen atmosphere at room temperature for 11 hours.After completion of the reaction, a saturated aqueous sodium chloridesolution was added to the reaction mixture, and then extracted withchloroform. The extract was dried over Na₂SO₄, filtered and concentratedin vacuo, and the thus obtained crude product was purified by a silicagel column chromatography (AcOEt:hexane=1:2) to obtain 2.75 g of thetitle compound dimethyl8-benzyloxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate.The yield from the above two steps was 87 mol %.

[0091] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); ¹H-NMR (CDCl₃,300 MHz): δ 11.7(s, 0.25H), 7.40-7.30(m,5H), 5.23-4.70(m, 4H), 3.82-3.59(m, 6H), 3.44(s, 1H), 3.10(s, 0.25H),3.09(s, 0.5H), 2.40-1.56(m, 4H); IR (CHCl₃): 1739, 1701, 1662, 1618,1498, 1444, 1436, 1425, 1369, 1336, 1319, 1303, 1290, 1265, 1244 cm⁻¹;MS(FAB) m/z 376(M⁺+H, 57); HRMS(FAB) C₁₉H₂₂NO₇ (M⁺+H): Calcd. 376.1397,Found 376.1395.

EXAMPLE 4

[0092] Synthesis of dimethyl 8-t-butoxycarbonyl-3-oxo-8-azabicyclor[3.2.1]octane-2-4-dicarboxylate (1i: R′=Boc and R=Me in the formula (1))

[0093] To a solution in chloroform (30 ml) of the debenzylatedderivative dimethyl 3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate(1.37 g, 5.62 mmol) obtained in Example 3 were added di-t-butyldicarbonate (1.55 ml, 6.75 mmol) and triethylamine (0.94 ml, 6.75 mmol),and the resulting mixture was stirred under a nitrogen atmospere at roomtemperature. After completion of the reaction, a saturated aqueoussodium chloride solution was added to the reaction mixture, and thenextracted with chloroform. The extract was dried over Na₂SO₄, filteredand then concentrated in vacuo, and the thus obtained crude product waspurified by a silica gel column chromatography (AcOEt:hexane=1:5) toobtain 1.90 g of the title compound dimethyl8-t-butoxycarbonyl-3-oxo-8-azabicyclo[3,2,1]-octane-2,4-dicarboxylate.The yield was 98 mol %.

[0094] Colorless needles (a mixture of tautomers and concurrent-lystereoisomers); mp 89-90° C.(AcOEt/hexane=1/4); ¹H-NMR (CDCl₃, 300 MHz):δ 11.9(s, 0.2H), 11.8(s, 0.3H), 5.03-4.58(m br, 1.8H), 4.16(d, J=3.7 Hz,0.2H), 3.82-3.66(m, 6H), 3.49(s, 0.25H), 3.33(s, 0.25H), 3.07(s, 0.5H),2.31-1.78(m, 2.5H), 1.69-1.59(m, 1H), 1.54-1.22(m, 10H); IR (KBr): 1743,1693, 1654, 1622, 1439, 1417, 1390, 1367, 1336, 1298, 1276, 1224, 1207,1161, 1105, 1049, 1020 cm⁻¹; MS(FAB) m/z 342(M⁺+H, 44); HRMS(FAB)C₁₆H₂₄NO₇ (M⁺+H): Calcd. 342.1553, Found 342.1555; Elemental analysisCalcd. C₁₆H₂₃NO₇: C, 56.30; H, 6.79; N, 4.10. Found: C, 56.38; H, 6.94;N, 4.08.

EXAMPLE 5

[0095] Synthesis of methyl8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate (2a: R′=Me andR=Me in the formula (2))

[0096] Lipase PS (3.79 g) was added to a mixture of the dimethyl8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1a) (430 mg,1.68 mmol) of obtained in Example 1, toluene (10 ml) and 0.3 M phosphatebuffer (pH=7.2, 10 ml), and the resulting mixture was stirred at roomtemperature for 3 days. After completion of the reaction, the reactionmixture was heated at 80° C. for 10 minutes and filtered with Celite,and the filtrate was adjusted to pH 8-8.5 with a saturated aqueoussodium hydrogencarbonate solution and extracted with chloroform. Theextract was dried over Na₂SO₄, filtered and concentrated in vacuo, andthe thus obtained crude product was purified by a silica gel columnchromatography (CHCl₃:MeOH=40:1) to obtain 161 mg of methyl8-methyl-3-oxo-8-azabicyclo[3.2.1]-octane-2-carboxylate. The yield was48.5 mol %. Reaction was carried out in the same manner as above exceptfor using each of lipase A, lipase M, lipase AY, lipase F-AP-15, lipaseAK, porcine pancreas lipase (PPL), etc. in place of lipase PS, to givean yield of 30 to 50 mol %. All the reaction products, however, wereoptically inactive monoester compounds.

[0097] Colorless needles (a mixture of tautomers and concurrentlystereoisomers); Optical purity 0% ee; ¹H-NMR (CDCl₃, 300 MHz): δ 11.8(sbr, 0.2H), 3.89-3.70(m, 5H), 3.65-3.60(m, 0.15H), 3.52-3.45(m, 0.15H),3.40-3.30(m, 0.5H), 2.85-2.68(m, 1H), 2.53(s, 0.75H), 2.37(s, 0.3H),2.35(s, 2.1H), 2.26-2.05(m, 3H), 1.92-1.86(m, 0.5H), 1.82-1.75(m, 0.5H),1.64-1.50(m, 1H); IR (CHCl₃): 3689, 1716, 1444, 1303, 1234, 1203 cm⁻¹;MS(FAB) m/z 198(M⁺+H, 100); HRMS(FAB) C₁₀H₁₆NO₃ (M⁺+H): Calcd. 198.1130,Found 198.1138; Elemental analysis C₁₀H₁₅NO₃ Calcd.: C, 60.90; H, 7.67;N, 7.10. Found: C, 60.70; H, 7.73; N, 7.16.

EXAMPLE 6

[0098] Synthesis of methyl(1R,5S)-8-benzyl-3-oxo-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2b:R′=Bn and R=Me in the formula (2))

[0099] Using each of various enzymes, asymmetric demethoxycarbonylationof dimethyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylatewas carried out by the following methods (A), (B) and (C).

[0100] (A) Synthesis using lipase:

[0101] According to the method described in Example 5, stirring wasconducted for 8 days under the following conditions: PPL 300 mg/100 mgsubstrate, toluene-0.3 M phosphate buffer (pH=7.2), 35° C. An yield of28 mol % was attained but the optical purity was 0% ee.

[0102] (B) Synthesis Using PLE:

[0103] To a solution of dimethyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (5.00 g, 15.1mmol) of in 0.1 M phosphate buffer (pH=8.0, 150 ml) was added PLE (794mg, 1,000 units/mmol), and the resulting mixture was stirred at roomtemperature for 24 hours. After completion, of the reaction, thereaction mixture was filtered with Celite and the filtrate was extractedwith chloroform. The extract was dried over Na₂SO₄, filtered and thenconcentrated in vacuo, and the thus obtained crude product was purifiedby a silica gel column chromatography (AcOEt:hexane=1:8) to obtain 644mg of the title compound methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate. Theyield was 20 mol %.

[0104] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); [α]_(D) ²⁶-9.81(c 1.60, CHCl₃); Optical purity 43% ee;¹H-NMR (CDCl₃, 300 MHz): δ 11.8(s, 0.4H), 7.42-7.23(m, 5H), 3.85-3.76(m,1H), 3.74(s, 2H), 3.72(s, 1H), 3.64(s, 1.33H), 3.62(s, 0.67H),3.61-3.47(m, 1H), 3.37(t, J=5.7 Hz, 1H), 3.12(t, J=2.0 Hz, 0.3H),2.97-2.90(m, 0.3H), 2.80-2.69(m, 1H), 2.32-2.03(m, 2H), 1.92-1.49(m,2H); IR (CHCl₃): 3690, 1736, 1713, 1655, 1445, 1350, 1221, 1217 cm⁻¹;MS(FAB) m/z 274(M⁺+H, 100); HRMS(FAB) C₁₆H₂₁NO₃ (M⁺+H): Calcd. 274.1443,Found 274.1433.

[0105] (C) Synthesis Using Baker's Yeast

[0106] To a baker's yeast aqueous solution (50 ml) was added sucrose(4.14 g), and the mixture was stirred at 35° C. for 30 minutes. Afterthe stirring, the thus obtained solution was added to dimethyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (457 mg, 1.38mmol) of, and the resulting mixture was stirred at 35° C. for 2 days.After completion of the reaction, the reaction mixture was filtered withCelite and the filtrate was extracted with chloroform. The extract wasdried over Na₂SO₄, filtered and then concentrated in vacuo, and the thusobtained crude product was purified by a silica gel columnchromatography (AcOEt:hexane=1:8) to obtain 61.6 mg of the titlecompound methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate. Theyield was 16 mol %.

[0107] Light-yellow oil; [α]_(D) ¹⁹+1.94(c 1.12, CHCl₃; Optical purity6% ee.

[0108] In the same manner as above, asymmetric demethoxycarbonylation ofeach of tropinonedicarboxylic acid methyl esters obtained by convertingthe amino-protecting group R′ of the compounds obtained in Examples 1 to4 above to a Boc group or a Z group was attempted using each of enzymessuch as lipase A, lipase M, lipase AY, lipase F-AP-15, lipase PS, lipaseAS, PPL, PLE, B.Y., etc. No optically active tropinonemonocarboxylicacid ester was obtained in any case.

EXAMPLE 7

[0109] Synthesis of diethyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1c: R′=Bn and R=Et in the formula (1))

[0110] To an aqueous solution (30 ml) of 2,5-dimethoxytetrahydrofuran(6.48 ml, 50 mmol) of was added concentrated hydrochloric acid (4 ml),and the resulting mixture was stirred at room temperature for 2.5 hours.After completion of the reaction, the reaction solution was neutralizedwith potassium carbonate and the excess methanol was evapolated underreduced pressure. The residue was extracted by using an Extrelut column,a column for extraction, with chloroform. The chloroform extractsolution was dried over MS4A and magnesium sulfate, filtered and thenconcentrated in vacuo, whereby a crude product of succindialdehyde wasobtained. A methanol (15 ml) solution of benzylamine (9.08 ml, 50 mmol)was added dropwise to a methanol (15 ml) solution of the obtainedsuccindialdehyde in an ice bath, and the reaction mixture was stirredfor 2 hours. Then, a methanol (15 ml) solution of diethyl1,3-acetonedicarboxylate (5.46 ml, 50 mmol) of was added dropwisethereto in an ice bath and the reaction mixture was stirred foradditional 16 hours. After completion of the reaction, the solvent wasevapolated under reduced pressure and the thus obtained crude productwas purified by a silica gel column chromatography (acetone:hexane=1:5)to obtain 14.7 g of the title compound diethyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate. The yieldwas 82 mol %.

[0111] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); ¹H-NMR (CDCl₃, 300 MHz): δ 12.0(s, 0.25H), 11.9(s,0.25H), 7.36-7.24(m, 5H), 4.32-3.57(m, 8H), 3.36(s, 0.33H), 3.31(s,0.33H), 3.16(d, J=2.5 Hz, 0.33H), 2.93(d, J=1.2 Hz, 0.5H), 2.25-1.77(m,4H), 1.34-1.03(m, 6H); IR (CHCl₃): 1732, 1654, 1622, 1321, 1301, 1261,1230, 1182, 1092 cm⁻¹; MS(FAB) m/z 360(M⁺H, 100); HRMS(FAB) C₂₀H₂₆NO₅(M⁺+H): Calcd. 360.1811, Found 360.1821.

EXAMPLE 8

[0112] Synthesis of diisopropyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1d: R′=Bnand R=i−Pr in the formula (1))

[0113] To an aqueous solution (30 ml) of 2,5-dimethoxytetrahydrofuran(6.48 ml, 50 mmol) was added concentrated hydrochloric acid (4 ml), andthe resulting mixture was stirred at room temperature for 2.5 hours.After completion of the reaction, the reaction solution was neutralizedwith potassium carbonate and the excess methanol was evapolated underreduced pressure. The residue was extracted by using an Extrelut column,a column for extraction, with chloroform. The chloroform extractsolution was dried over MS4A and magnesium sulfate, filtered and thenconcentrated in vacuo, whereby a crude product of succindialdehyde wasobtained. Then, dimethyl 1,3-acetonedicarboxylate (7.2 ml, 50 mmol) wasadded to a sodium isopropoxide solution (38.3 ml) under a nitrogenatmosphere, and the resulting mixture was refluxed for 24 hours. Aftercompletion of the reaction, a saturated aqueous ammonium chloridesolution was added to the reaction mixture, followed by extraction withAcOEt. The extract was dried over MgSO₄, filtered and concentrated invacuo, whereby a crude product of diisopropyl 1,3-acetonedicarboxylatewas obtained.

[0114] Under a nitrogen atmosphere, a methanol (15 ml) solution ofbenzylamine (5.46 ml, 50 mmol) was added dropwise to a methanol (15 ml)solution of the obtained succindialdehyde in an ice bath, and theresulting mixture was stirred for 2 hours. Then, a methanol (15 ml)solution of the obtained diisopropyl 1,3-acetonedicarboxylate was addeddropwise thereto in an ice bath and the reaction mixture was stirred foradditional 19 hours. After completion of the reaction, the solvent wasevapolated under reduced presure and the thus obtained crude product waspurified by a silica gel column chromatography (AcOEt:hexane=1: 15) toobtain 1.42 g of the title compound diisopropyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate. The yieldwas 7.3 mol %.

[0115] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); ¹H-NMR (CDCl₃, 300 MHz): δ 12.1(s, 0.25H), 11.9(s,0.25H), 7.41-7.10(m, 5H), 5.17-4.98(m, 1.6H), 4.87(septet, J=6.2 Hz,0.4H), 4.00-3.55(m, 4H), 3.37(s, 0.25H), 3.32(s, 0.25H), 3.14(d, J=2.4Hz, 0.5H), 2.90(d, J=1.3 Hz, 0.5H), 2.28-1.62(m, 4H), 1.45-1.17(m, 10H),1.14(d, J=6.3 Hz, 1H), 0.87(d, J=6.3 Hz, 1H); IR (CHCl₃): 3689, 1782,1652, 1263, 1182, 1103 cm⁻¹; MS(FAB) m/z 388(M⁺+H, 39); HRMS(FAB)C₂₂H₃₀NO₅ (M⁺+H): Calcd. 388.2124, Found 388.2117.

EXAMPLE 9

[0116] Synthesis of dibutyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1d: R′=Bnand R=n−Bu in the formula (1))

[0117] To an aqueous solution (30 ml) of 2,5-dimethoxytetrahydrofuran(6.48 ml, 50 mmol) was added concentrated hydrochloric acid (4 ml), andthe resulting mixture was stirred at room temperature for 2.5 hours.After completion of the reaction, the reaction solution was neutralizedwith potassium carbonate and the excess methanol was evapolated underreduced pressure. The residue was extracted by using an Extrelut column,a column for extraction, with chloroform. The chloroform extractsolution was dried over MS4A and magnesium sulfate, filtered and thenconcentrated in vacuo, whereby a crude product of succindialdehyde wasobtained. Then, dimethyl 1,3-acetonedicarboxylate (7.2 ml, 50 mmol) wasadded to a sodium butoxide solution (60 ml) under a nitrogen atmosphere,and the resulting mixture was refluxed for 19 hours. After completion ofthe reaction, a saturated aqueous ammonium chloride solution was addedto the reaction mixture, followed by extraction with ethyl acetate. Theextract was dried over MgSO₄, filtered and concentrated in vacuo,whereby a crude product of dibutyl 1,3-acetonedicarboxylate wasobtained.

[0118] Under a nitrogen atmosphere, a methanol (15 ml) solution ofbenzylamine (5.46 ml, 50 mmol) was added dropwise to a methanol (15 ml)solution of the obtained succindialdehyde in an ice bath, and theresulting mixture was stirred for 2 hours. Then, a methanol (15 ml)solution of the obtained dibutyl 1,3-acetonedicarboxylate was addeddropwise thereto in an ice bath and the reaction mixture was stirred foradditional 13.5 hours. After completion of the reaction, the solvent wasevapolated under reduced pressure and the thus obtained crude productwas purified by a silica gel column chromatography (AcOEt: hexane=1:15)to obtain 4.77 g of the title compound dibutyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate. The yieldwas 23 mol %.

[0119] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); ¹H-NMR (CDCl₃, 300 MHz): δ 12.0(s, 0.2H), 11.8(s, 0.2H),7.39-7.24(m, 5H), 4.22-3.97(m, 4H), 3.90-3.58(m, 4H), 3.37(s, 0.8H),3.17(d, J=2.6 Hz, 0.4H), 2.94(d, J=1.5 Hz, 0.4H), 2.28-1.22(m, 12H),0.97-0.84(m, 6H); IR (CHCl₃): 1732, 1654, 1622, 1321, 1301, 1257, 1180cm⁻¹; MS(FAB) m/z 416(M⁺+H, 28); HRMS(FAB) C₂₄H₃₄NO₅ (M⁺+H): Calcd.416.2451, Found 416.2444.

EXAMPLE 10

[0120] Synthesis of dibenzyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1f: R′=Bnand R=Bn in the formula (1))

[0121] To an aqueous solution (10 ml) of 2,5-dimethoxytetrahydrofuran(1.3 ml, 10 mmol) was added concentrated hydrochloric acid (1 ml), andthe resulting mixture was stirred at room temperature for 2.5 hours.After completion of the reaction, the reaction solution was neutralizedwith potassium carbonate and the excess methanol was evapolated underreduced pressure. The residue was extracted by using an Extrelut column,a column for extraction, with chloroform. The chloroform extractsolution was dried over MS4A and magnesium sulfate, filtered and thenconcentrated in vacuo, whereby a crude product of succindialdehyde wasobtained. Then, benzyl alcohol (10.9 ml, 100 mmol) and DMAP (a catalyst)were added to a solution of dimethyl 1,3-acetonedicarboxylate (1.44 ml,10 mmol) in toluene (30 ml) under a nitrogen atmosphere, and theresulting mixture was refluxed for 5 hours. After completion of thereaction, the excess solvent was evapolated under reduced pressure toobtain a crude product of dibenzyl 1,3-acetonedicarboxylate.

[0122] Under a nitrogen atmospere, a solution of benzylamine (1.10 ml,10 mmol) in benzyl alcohol (5 ml) was added dropwise to a solution ofthe obtained succindialdehyde in benzyl alcohol (5 ml) in an ice bath,and the reaction mixture was stirred for 2 hours. Then, a solution ofthe obtained dibenzyl 1,3-acetonedicarboxylate in benzyl alcohol (5 ml)was added dropwise thereto in an ice bath and the resulting mixture wasstirred for additional 16 hours. After completion of the reaction, thesolvent was evapolated under reduced pressure and the thus obtainedcrude product was purified by a silica gel column chromatography(AcOEt:hexane=1:15) to obtain 912 mg of the title compound dibenzyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate. The yieldwas 19 mol %.

[0123] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); ¹H-NMR (CDCl₃, 300 MHz): δ 11.9(s, 0.25H), 11.8(s,0.25H), 7.42-7.12(m, 15H), 5.27-4.80(m, 4H), 4.16-3.81(m, 2H),3.73-3.50(m, 2H), 3.39-3.31(m, 0.5H), 3.24(d, J=2.5 Hz, 0.5H), 3.00(d,J=1.4 Hz, 0.5H), 2.28-1.77(m, 4H); IR (CHCl₃): 1733, 1654, 1450, 1259,1230, 1166 cm⁻¹; MS(FAB) m/z 484(M⁺+H, 33); HRMS(FAB) C₃₀H₃₀NO₅ (M⁺+H):Calcd. 484.2124, Found 484.2129.

EXAMPLE 11

[0124] Synthesis of diethyl8-benzyloxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate(1g: R′=Z and R=Et in the formula (1))

[0125] Under a nitrogen atmosphere, benzyloxycarbonyl chloride (0.639ml, 4.48 mmol) and triethylamine (0.624 ml, 4.48 mmol) were added to asolution in chloroform (20 ml) of the diethyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate obtained inExample 3, and the resulting mixture was stirred at room temperature for22 hours. After completion of the reaction, a saturated aqueous sodiumchloride solution was added to the reaction mixture, and then extractedwith chloroform. The extract was dried over Na₂SO₄, filtered and thenconcentrated in vacuo, and the thus obtained crude product was purifiedby a silica gel column chromatography (AcOEt:hexane=1:10) to obtain 1.32g of the title compound diethyl8-benzyloxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate.The yield was 88 mol %.

[0126] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); ¹H-NMR (CDCl₃, 300 MHz): δ 12.0(s, 0.1H), 11.8(s, 0.4H),7.61-7.28(m, 5H), 5.23-4.64(m, 4H), 4.31-4.09(m, 4H), 4.01-3.84(m,0.75H), 3.32(s br, 0.25H), 3.08(s br, 0.5H), 2.35-1.82(m, 3H),1.72-1.53(m, 1H), 1.36-1.06(m, 6H); IR (CHCl₃): 3689, 1733, 1701, 1658,1602, 1472, 1265, 1242, 1180, 1105 cm⁻¹; MS(FAB) m/z 404(M⁺+H, 65);HRMS(FAB) C₂₁H₂₆NO₇ (M⁺+H): Calcd. 404.1739, Found 404.1746.

EXAMPLE 12

[0127] Synthesis of ethyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2c:R′=Bn and R=Et in the formula (2))

[0128] To a solution of diethyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (993.3 mg,2.76 mmol) in 0.1 M phosphate buffer (pH=8.0, 27.6 ml) was added PLE(726.3 mg, 5000 units/mmol), and the resulting mixture was stirred atroom temperature for 24 hours. After completion of the reaction, thereaction mixture was filtered with Celite and the filtrate was extractedwith chloroform. The extract was dried over Na₂SO₄, filtered and thenconcentrated in vacuo, and the thus obtained crude product was purifiedby a silica gel column chromatography (chloroform: methanol=100:1) toobtain 396.4 mg of the title compound ethyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate. Theyield was 50 mol %.

[0129] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); [α]_(D) ²¹-9.09(c 1.66, CHCl₃); Optical purity 93% ee;¹H-NMR (CDCl₃, 300 MHz): δ 11.9(s, 0.3H), 7.44-7.22(m, 5H), 4.29-3.97(m,2H), 3.88-3.43(m, 4H), 3.39-3.36(m, 0.4H), 3.11(t, J=2.0 Hz, 0.3H),2.96-2.89(m, 0.5H), 2.80-2.60(m, 1H), 2.31-2.03(m, 2.5H), 1.92-1.75(m,1H), 1.69-1.49(m, 1H), 1.38-1.04(m, 3H); IR (CHCl₃): 1732, 1714, 1647,1604, 1301, 1236, 1224 cm⁻¹; MS(FAB) m/z 288(M⁺+H, 100); HRMS(FAB)C₁₇H₂₂NO₃ (M⁺+H): Calcd. 288.1599, Found 288.1590.

[0130] The same experiment as above was carried out except for changingthe stirring time to 3 hours or 48 hours. When the stirring time was 3hours, the yield was 30 mol % and the optical purity 95% ee. When thestirring time was 48 hours, the yield was 7 mol % and the optical purity97% ee.

EXAMPLE 13

[0131] Synthesis of isopropyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2d:R′=Bn and R=i−Pr in the formula(2))

[0132] To a solution in 0.1 M phosphate buffer (pH 8.0, 72 ml) of thediisopropyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate(1d) (1.4 g, 3.61 mmol) obtained in Example 8 was added PLE (950 mg,5000 units/mmol), and the resulting mixture was stirred at roomtemperature for 24 hours. After completion of the reaction, the reactionmixture was filtered with Celite and the filtrate was extracted withchloroform. The extract was dried over Na₂SO₄, filtered and thenconcentrated in vacuo, and the thus obtained crude product was purifiedby a silica gel column chromatography (chloroform:methanol=200:1) toobtain 159 mg of the title compound isopropyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate. Theyield was 15 mol % and the optical purity 63% ee.

[0133] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); [α]_(D) ²⁴ -11.1(c 1.18, CHCl₃); Optical purity 63% ee;¹H-NMR (CDCl₃, 300 MHz): δ 12.0(s, 0.3H), 7.43-7.23(m, 5H), 5.14-4.99(m,1H), 3.93-3.49(m, 4H), 3.45-3.35(m, 0.9H), 3.11(t, J=2.1 Hz, 0.3H),2.89-2.71(m, 1H), 2.28-2.03(m, 2.5H), 1.92-1.49(m, 2H), 1.33-1.14(m,6H); IR (CHCl₃): 1732, 1716, 1647, 1602, 1284, 1234, 1105 cm⁻¹; MS(FAB)m/z 302(M⁺+H, 34); HRMS(FAB) C₁₈H₂₄NO₃ (M⁺+H): Calcd. 302.1757, Found302.1764.

EXAMPLE 14

[0134] Synthesis of butyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2e:R′=Bn and R=Bu in the formula (2))

[0135] To a solution in 0.1 M phosphate buffer (pH 8.0, 200 ml) of thedibutyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1e)(8.37 g, 20.1 mmol) obtained in Example 9 was added PLE (5.3 g, 5000units/mmol) of, and the resulting mixture was stirred at roomtemperature for 24 hours. After completion of the reaction, the reactionmixture was filtered with Celite and the filtrate was extracted withchloroform. The extract was dried over Na₂SO₄, filtered and thenconcentrated in vacuo, and the thus obtained crude product was purifiedby a silica gel column chromatography (AcOEt:hexane=1:10) to obtain 3.23g of the title compound butyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate. Theyield was 51 mol % and the optical purity 95% ee.

[0136] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); [α]_(D) ²⁵-9.38(c 0.71, CHCl₃); Optical purity 95% ee;¹H-NMR (CDCl₃, 300 MHz): δ 11.9(s, 0.4H), 7.42-7.21(m, 5H), 4.23-4.07(m,2H), 4.01-3.34(m, 4.3H), 3.12(t, J=2.1 Hz, 0.3H), 2.94-2.69(m, 1H),2.30-2.04(m, 2H), 1.92-1.23(m, 7H), 0.95-0.88(m, 3H); IR (CHCl₃): 1732,1714, 1647, 1604, 1299, 1234 cm⁻¹; MS(FAB) m/z 316(M⁺+H, 42); HRMS(FAB)C₁₉H₂₆NO₃ (M⁺+H): Calcd. 316.1913, Found 316.1905.

EXAMPLE 15

[0137] Synthesis of benzyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate((−)-2f:R′=Bn and R=Bn in the formula(2))

[0138] To a solution in 0.1 M phosphate buffer (pH=8.0, 35 ml) of thedibenzyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate (1f)(779 mg, 1.61 mmol) obtained in Example 10 was added PLE (424 mg, 5000units/mmol), and the resulting mixture was stirred at room temperaturefor 24 hours. After completion of the reaction, the reaction mixture wasfiltered with Celite and the filtrate was extracted with chloroform. Theextract was dried over Na₂SO₄, filtered and then concentrated in vacuo,and the thus obtained crude product was purified by a silica gel columnchromatography (chloroform:methanol=100:1) to obtain 287 mg of the titlecompound benzyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate. Theyield was 51 mol % and the optical purity 74% ee.

[0139] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); [α]_(D) ²⁷-7.74(c 1.23, CHCl₃); Optical purity 74% ee;¹H-NMR (CDCl₃, 300 MHz): δ 11.8(s, 0.1H), 7.47-7.16(m, 10H),5.27-4.80(m, 0.67H), 4.70(s, 1.33H), 3.92-3.56(m, 4H), 3.51-3.37(m,0.75H), 3.18(t, J=2.1 Hz, 0.67H), 2.87-2.66(m, 2H), 2.28-2.02(m, 2H),1.93-1.52(m, 2H); IR (CHCl₃): 1735, 1716, 1651, 1612, 1454, 1396, 1298,1235, 1174, 1166, 1132 cm⁻¹; MS(FAB) m/z 350(M⁺+H, 37); HRMS(FAB)C₂₂H₂₄NO₃ (M⁺+H): Calcd. 350.1756, Found 350.1760.

EXAMPLE 16

[0140] Synthesis of ethyl(1R,5S)-8-benzyloxy-carbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate((−)-2g: R′=Z and R=Et in the formula(2))

[0141] To a solution in 0.1 M phosphate buffer (pH=8.0, 30 ml) of thediethyl8-benzyloxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2,4-dicarboxylate(1g) (404 mg, 1.00 mmol) obtained in Example 11 was added PLE (263 mg,5000 units/mmol), and the resulting mixture was stirred at roomtemperature for 24 hours. After completion of the reaction, the reactionmixture was filtered with Celite and the filtrate was extracted withchloroform. The extract was dried over Na₂SO₄, filtered and thenconcentrated in vacuo, and the thus obtained crude product was purifiedby a silica gel column chromatography (chloroform:methanol=100:1) toobtain 100 mg of the title compound ethyl(1R,5S)-8-benzyloxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate.The yield was 30 mol %.

[0142] Light-yellow oil (a mixture of tautomers and concurrentlystereoisomers); [α]_(D) ²⁶+0.89(c 1.08, CHCl₃); ¹H-NMR (CDCl₃, 300 MHz):δ 11.9(s, 0.2H), 7.49-7.27(m, 5H), 5.22-5.13(m, 4H), 4.95(s br, 0.8H),4.70-4.57(m br, 0.67H), 4.47(s br, 0.33H), 4.27-4.20(m, 2H), 3.27(s,1H), 2.43-1.85(m, 4H), 1.76-1.61(m, 2H), 1.33-1.06(m, 3H); IR (CHCl₃):3689, 1697, 1419, 1338, 1321, 1284, 1191, 1099, 1004 cm⁻¹; MS(FAB) m/z332(M⁺+H, 24); HRMS(FAB) C₁₈H₂₂NO₅ (M⁺+H): Calcd. 332.1548, Found332.1501.

[0143] Table 1 summarizes the results of the enzyme-catalyzed asymmetricdealkoxycarbonylations of each tropinonedi-carboxylic acid ester whichare described in Examples 5 to 16. Optical Example Substrate R′ RProduct Conditions Enzyme Time Yield purity  5 1a Me Me 2a A Lipase^(a)) 3 day 30-50 mol %  0% ee  6A 1b Bn Me 2b A PPL ^(b)) 8 day 28 mol%  0% ee  6B 1b Bn Me (−)−2b B PLE ^(c)) 24 hr 20 mol % 43% ee  6C 1b BnMe (−)−2b C B.Y. ^(d)) 2 day 16 mol %  6% ee 12 1c Bn Et — A PPL ^(e)) 5day 0 mol % — 12 1c Bn Et (−)−2c B PLE ^(f)) 3 hr 30 mol % 95% ee 12 1cBn Et (−)−2c B PLE ^(f)) 24 hr 50 mol % 93% ee 12 1c Bn Et (−)−2c B PLE^(f)) 48 hr 7 mol % 97% ee 13 1d Bn i-Pr (−)−2d B PLE ^(f)) 24 hr 15 mol% 63% ee 14 1e Bn n-Bu (−)−2e B PLE ^(f)) 24 hr 34 mol % 95% ee 15 1f BnBn (−)−2f B PLE ^(f)) 24 hr 51 mol % 74% ee 16 1f Z Et (−)−2g B PLE^(f)) 24 hr 30 mol % —

[0144] Asymetric dealkoxycarbonylation of tropinonedicarboxylic acidesters

EXAMPLE 17

[0145] Synthesis of methyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate (dl-form)

[0146] To a solution dimethyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate (23.6 g, 71.2mmol) in THF (100 ml) was added an aqueous solution (100 ml) of LiOH.H₂O(7.47 g, 178 mmol), and the resulting mixture was stirred at roomtemperature. After 36 hours, the reaction mixture was adjusted to pH 2with 2N-HCl and stirred. After 1 day, the stirred reaction mixture wasadjusted to pH 8-8.5 with a saturated aqueous sodium hydrogencarbonatesolution and extracted with chloroform. The extract was dried overNa₂SO₄, filtered and then concentrated in vacuo, and the thus obtainedcrude product was purified by a silica gel column chromatography(AcOEt:hexane=1:5) to obtain 18.3 g of the title compound methyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate. The yield was 94mol %.

EXAMPLE 18

[0147] Synthesis of methyl8-benzyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate (dl-form)

[0148] In an ice bath, NaBH₄ (412 mg, 10.6 mmol) was added to a methanol(55 ml) solution of the methyl8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate (1.45 g, 5.32mmol) obtained in Example 17, and the mixture was stirred for 14.5hours. After completion of the reaction, a saturated aqueous ammoniumchloride solution was added to the reaction mixture and the excesssolvent was evapolated under reduced pressure. The residue was adjustedto pH 8.0-8.5 with a saturated aqueous sodium hydrogencarbonate solutionand extracted with chloroform. The extract was dried over Na₂SO₄lfiltered and then concentrated in vacuo, and the resulting residue wasdissolved in chloroform (30 ml) under a nitrogen atmosphere. To theresulting solution were added triethylamine (1.48 ml, 10.6 mmol) andDMAP as a catalyst, and trifluoroacetic anhydride (1.13 ml, 7.98 mmol)was added thereto in an ice bath, and then the resulting mixture wasstirred at room temperature for 21 hours. After completion of thereaction, the reaction mixture was adjusted to pH 9.0 with a saturatedaqueous sodium hydrogencarbonate solution and extracted with chloroform.The extract was dried over Na₂SO₄, filtered and then concentrated invacuo, and the thus obtained crude product was purified by a silica gelcolumn chromatography (AcOEt:hexane=1:8) to obtain 577 mg of the titlecompound methyl 8-benzyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate.The yield from the above two steps was 42 mol %. The compound obtainedin the present example was a dl-form and was used as a referencestandard compound for optical purity measurement.

[0149] Light-yellow oil; ¹H-NMR (CDCl₃, 300 MHz): δ 7.37-7.21(m, 5H),6.90-6.88(m, 1H), 3.82(d, J=6.1 Hz, 1H), 3.73(s, 3H), 3.62(s, 2H),3.29-3.26(m, 1H), 2.66-2.59(d br, J=20 Hz, 1H), 2.15-2.09(m, 2H),1.88-1.78(m, 2H), 1.54-1.48(m, 1H); IR (CHCl₃): 1705, 1638, 1603, 1437,1283, 1259, 1086 cm⁻¹; MS(FAB) m/z 258(M⁺+H, 100); HRMS(FAB) C₁₆H₂₀NO₂(M⁺+H): Calcd. 258.1509, Found 258.1504.

EXAMPLE 19

[0150] Synthesis of methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2b:R′=Bn and R=Me in the formula(2))

[0151] (1) Synthesis from ethyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2c:R′=Bn and R=Et in the formula (2))

[0152] Under a nitrogen atmosphere, sodium methoxide (50 ml) was addedto ethyl (1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate(113 mg, 0.375 mmol), and the resulting mixture was refluxed for 2 days.After completion of the reaction, a saturated aqueous ammonium chloridesolution was added to the reaction mixture and the excess solvent wasevapolated under reduced pressure. The residue was adjusted to pH8.0-8.5 with a saturated aqueous sodium hydrogencarbonate solution andextracted with chloroform. The extract was dried over Na₂SO₄, filteredand then concentrated in vacuo, and the thus obtained crude product waspurified by a silica gel column chromatography (AcOEt:hexane=1:5) toobtain 1.10 g of the title compound methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate. Theyield was 95 mol %.

[0153] (2) In the same manner as above, the title compound methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo-[3.2.1]octane-2-carboxylate wasobtained also from each of the compounds (−)-2d, (−)-2e and (−)-2f eachof which had a substituent different from that of the compound (−)-2b.

EXAMPLE 20

[0154] Synthesis of methyl(1R,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate (thecompound A in the reaction scheme E)

[0155] Under a nitrogen atmosphere, NaBH₄ (69.6 mg, 1.84 mmol) was addedto a methanol (10 ml) solution of the methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2b)(264 mg, 0.92 mmol) obtained in Example 19, in an ice bath, and thereaction mixture was stirred for 2 hours. After completion of thereaction, a saturated aqueous ammonium chloride solution was added tothe reaction mixture and the excess solvent was evapolated under reducedpressure. The residue was adjusted to pH 8.0-8.5 with a saturatedaqueous sodium hydrogencarbonate solution and extracted with chloroform.The extract was dried over Na₂SO₄, filtered and then concentrated invacuo. Then, the residue was dissolved in chloroform (10 ml) under anitrogen atmosphere, and triethylamine (267 μl, 1.91 mmol) and DMAP as acatalyst were added thereto. In an ice bath, trifluoroacetic anhydride(203 μl, 1.44 mmol) was added thereto and the resulting mixture wasstirred at room temperature for 44 hours. After completion of thereaction, the reaction mixture was adjusted to pH 8.0-8.5 with asaturated aqueous sodium hydrogencarbonate solution and extracted withchloroform. The extract was dried over Na₂SO₄, filtered and thenconcentrated in vacuo, and the thus obtained crude product was purifiedby a silica gel column chromatography (AcOEt:hexane=1:5) to obtain 192.2mg of the title compound methyl(1R,5S)-8-benzyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate. The yieldfrom the above two steps was 81 mol %.

[0156] Light-yellow oil; [α]_(D) ²³-17.8(c 0.71, CHCl₃); Optical purity95% ee; Chiral HPLC analysis [DAICEL CHIRALCEL OD(25×0.46); eluent:n-hexane/2-propanol=100/1; flow rate: 0.3 ml/min; temperature: 25° C.;detector: 254 nm; (−)-A; 34.3 min, (+)-A; 38.0 min] ¹H-NMR (CDCl₃, 300MHz): δ 7.37-7.21(m, 5H), 6.90-6.88(m, 1H), 3.82(d, J=6.1 Hz, 1H),3.73(s, 3H), 3.62(s, 2H), 3.29-3.26(m, 1H), 2.66-2.59(d br, J=20 Hz,1H), 2.15-2.09(m, 2H), 1.88-1.78(m, 2H), 1.54-1.48(m, 1H); 1R (CHCl₃):1705, 1638, 1603, 1437, 1283, 1259, 1086 cm⁻¹; MS(FAB) m/z 258(M⁺+H,100); HRMS(FAB) C₁₆H₂₀NO₂ (M⁺+H): Calcd. 258.1509, Found 258.1504.

EXAMPLE 21

[0157] Synthesis of methyl(1R,5S)-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate (thecompound (+)-B in the reaction scheme F)

[0158] To a solution of methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2b)(818 mg, 2.99 mmol) in acetic acid (10 ml) was added 10% Pd—C (acatalyst), and the resulting mixture was stirred under a hydrogenatmosphere for 10 hours. After completion of the reaction, the mixturewas filtered with Celite and the filtrate was concentrated in vacuo. Theresidue was adjusted to pH 8.0-8.5 with a saturated aqueous sodiumhydrogen-carbonate solution and extracted with chloroform. The extractwas dried over Na₂SO₄, filtered and then concentrated in vacuo, and thethus obtained crude product was purified by a silica gel columnchromatography (CHC1₃:MeOH=30:1) to obtain 536.5 mg of methyl(1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate. In this case, theyield was 98 mol %. Then, to a methanol (20 ml) solution of thiscompound (281 mg, 1.54 mmol) were added a 37% formaldehyde solution (213μl, 7.67 mmol), formic acid (579 μl, 15.4 mmol) and paraformaldehyde(200 mg), and the resulting mixture was refluxed for 17 hours. Aftercompletion of the reaction, the reaction mixture was adjusted to pH8.0-8.5 with a saturated aqueous sodium hydrogencarbonate solution andextracted with chloroform. The extract was dried over Na₂SO₄, filteredand then concentrated in vacuo, and the thus obtained crude product waspurified by a silica gel column chromatography (CHCl₃:MeOH=50:1) toobtain 274 mg of methyl(1R,5S)-8-methyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate. Theyield from the above two steps was 88 mol %.

[0159] Light-yellow oil; [α]_(D) ²² +19.4(c 0.47, MeOH).

EXAMPLE 22

[0160] Synthesis of methyl(1R,5S)-8-t-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]-octane-2-carboxylate((−)-2ho R′=Boc and R=Me in the formula(2))

[0161] To a solution in acetic acid (5 ml) of the methyl(1R,5S)-8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate ((−)-2b)(188 mg, 0.69 mmol) obtained in Example 19 was added 10% Pd—C (acatalyst), and the resulting mixture was stirred under a hydrogenatmosphere for 7 hours. After completion of the reaction, the mixturewas filtered with Celite and the solvent was evapolated under reducedpressure. The residue was adjusted to pH 8.0-8.5 with a saturatedaqueous sodium hydrogencarbonate solution and extracted with chloroform.The extract was dried over Na₂SO₄, filtered and then concentrated invacuo, and the resulting residue was dissolved in chloroform.-Di-t-butyl dicarbonate (156 μl, 0.677 mmol) and triethylamine (94.4 μl,0.677 mmol) were added thereto, and the resulting mixture was stirred atroom temperature for 4 hours. After completion of the reaction, asaturated aqueous sodium chloride solution was added to the reactionmixture, and then extracted with chloroform. The extract was dried overNa₂SO₄, filtered and then concentrated in vacuo, and the thus obtainedcrude product was purified by a silica gel column chromatography(AcOEt:hexane=1:8) to obtain 127 mg of the title compound methyl(1R,5S)-8-t-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate.The yield from the above two steps was 73 mol %.

[0162] Light-yellow oil; [α]_(D) ²⁷-30.9(c 0.78, CHCl₃); ¹H-NMR (CDCl₃,300 MHz): δ 11.8(s, 0.33H), 4.85(s br, 1H), 4.36(m br, 1H), 3.78(s, 1H),3.77(s, 1H), 3.71(s, 1H), 3.26(s, 0.33H), 3.09-3.01(m, 0.67H),2.42-1.81(m, 3.67H), 1.70-1.56(m, 2H), 1.51(s, 2H), 1.47(s, 3.5H),1.45(s, 3.5H); MS(FAB) m/z 283(M⁺+H, 18); IR (CH₃Cl): 1811, 1755, 1691,1396, 1373, 1340, 1315, 1286, 1261, 1226, 1203, 1164, 1120, 1074 cm⁻¹;HRMS(FAB) C₁₄H₂₂NO₅ (M⁺+H): Calcd. 284.1498, Found 284.1493.

EXAMPLE 23

[0163] Synthesis of methyl(1R,5S)-8-t-butoxy-carbonyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate((−)-6a: R′=Boc and R=Me in the formula(6))

[0164] Under a nitrogen atmosphere, NaBH₄ (6.84 mg, 0.18 mmol) was addedto a methanol (3 ml) solution of the methyl(1R,5S)-8-t-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate((−)-2h) (25.6 mg, 0.09 mmol) obtained in Example 22, in an ice bath,and the reaction mixture was stirred for 3 hours. After completion ofthe reaction, a saturated aqueous ammonium chloride solution was addedto the reaction mixture and the excess solvent was evapolated underreduced pressure. The residue was adjusted to pH 8.0-8.5 with asaturated aqueous sodium hydrogencarbonate solution and extracted withchloroform. The extract was dried over Na₂SO₄, filtered and thenconcentrated in vacuo. Then, the residue was dissolved in chloroform (10ml) under a nitrogen atmosphere, and triethylamine (50.4 μl, 0.361 mmol)and DMAP (a catalyst) were added thereto. In an ice bath,trifluoroacetic anhydride (25.5 μl, 0.181 mmol) was added thereto andthe resulting mixture was stirred at room temperature for 36 hours.After completion of the reaction, the reaction mixture was adjusted topH 8.0-8.5 with a saturated aqueous sodium hydrogencarbonate solutionand extracted with chloroform. The extract was dried over Na₂SO₄,filtered and then concentrated in vacuo, and the thus obtained crudeproduct was purified by preparative-TLC (AcOEt:hexane=1:2) to obtain 6.8mg of the title compound methyl(1R,5S)-8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate.The yield from the above two steps was 28 mol %. The optical rotatorypower of the methyl(1R,5S)-8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylateobtained here is in good agreement with the value described inliterature, [α]_(D) ²¹-52.4(c 1.00, CHCl₃). By the purification bypreparative-TLC for separation, an optical purity of 95% ee wasattained, and the compound was colorless needles (mp 79-80° C.) andcould easily be further increased in optical purity by purification byrecrystallization.

[0165] Colorless needles; mp 79-80° C.(AcEt/hexane=¼); [α]_(D) ²⁶-60.2(c1.63, CHCl₃); Optical purity 95% ee; Chiral HPLC analysis [DAICELCH1RALCEL OD(25×0.46); eluent: n-hexane/2-propanol=100/1; flow rate: 0.5ml/min; temperature: 25° C.; detector: 254 nm; (−)-6a; 20.5 min, (+)-6a;24.9 min]; ¹H-NMR (CDCl₃, 300 MHz): δ 6.78-6.75(m, 1H), 4.83-4.78(m,1H), 4.37-4.28(m, 1H), 3.78(s, 3H), 2.89-2.81(m, 1H), 2.20-1.87(m, 4H),1.65-1.53(m, 1H), 1.44(s, 9H); IR (KBr): 1716, 1701, 1641, 1442, 1419,1380, 1369, 1340, 1323, 1259, 1224, 1164, 1105, 1089 cm⁻¹; MS(FAB) m/z268(M⁺+H, 19); HRMS(FAB) C₁₄H₂₂NO₄ (M⁺+H): Calcd. 268.1548, Found268.1552; Elemental analysis C₁₄H₂₁NO₄ Calcd.: C, 62.90; H, 7.92; N,5.24. Found: C, 62.69; H, 7.90; N, 5.53.

EXAMPLE 24

[0166] Synthesis of methyl(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate ((−)-6b:R′=Me and R=Me in the formula (6))

[0167] Under a nitrogen atmosphere, trifluoroacetic acid (TFA) (15 μl,0.196 mmol) was added to a solution in CH₂Cl₂ (2 ml) of the methyl(1R,5S)-8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate((−)-6a) (26.2 mg, 0.098 mmol) obtained in Example 23, in an ice bath,and the resalting mixture was stirred for 3 hours in an ice bath. Aftercompletion of the reaction, the excess solvent was evapolated underreduced pressure and the residue was dissolved in methanol (3 ml). Then,formaldehyde (a 37% aqueous solution, 22 μl, 0.294 mmol), formic acid(18 μl, 0.490 mmol) and paraformaldehyde (20 mg) as catalyst were addedthereto, and the resulting mixture was refluxed for 4 hours. After theexcess solvent was evapolated under reduced pressure, the residue wasadjusted to pH 8.0 with a saturated aqueous sodium hydrogencarbonatesolution and extracted with chloroform. The extract was dried overNa₂SO₄, filtered and then concentrated in vacuo, and the thus obtainedcrude product was purified by prepartive-TLC for separation(CHCl₃:MeOH=10:1) to obtain 6.9 mg of the title compound methyl(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate. The yieldwas 38.8 mol %.

[0168] Light-yellow oil; [α]_(D) ²¹-41.0(c 0.85, MeOH); ¹H-NMR (CDCl₃,300 MHz): δ 6.83-6.81(m, 1H), 3.79(d, J=5.4 Hz, 1H), 3.74(s, 3H),3.25(dd, J=3.0 and 2.5 Hz, 1H), 2.66-2.59(m, 1H), 2.35(s, 3H),2.27-2.11(m, 2H), 1.90-1.80(m, 2H), 1.55-1.48(m, 1H); IR (CHCl₃): 1708,1641, 1439, 1363, 1284, 1263 cm⁻¹; MS(FAB) m/z 290(M⁺+H, 39); HRMS(FAB)C₁₀H₁₆NO₂ (M⁺+H): Calcd. 182.1181, Found 182.1176.

INDUSTRIAL APPLICABILITY

[0169] According to the present invention, an optically activetropinonemonocarboxylic acid ester derivative useful as an intermediatefor synthesis of optically active tropane derivatives was obtained byreacting succindialdehyde with an organic amine and acetonedicarboxylicacid to obtain a tropinonedicarboxylic acid ester derivative, and thensubjecting this derivative to enzyme-catalyzed asymmetricdealkoxycarbonylation. Since anhydroecgonine methyl ester derived fromthe optically active tropinonemonocarboxylic acid ester derivative byreduction and dehydration had the same direction of optical rotation asin the case of anhydroecgonine methyl ester obtained from naturalcocaine, it was proved that the optically active tropinonemonocarboxylicacid ester derivative obtained had the same absolute configuration asthat of natural cocaine. The yield of the optically activetropinonemonocarboxylic acid ester derivative from the asymmetricdealkoxycarbonylation was 30 to 50 mol %, and its optical purity was 70to 97% ee. In addition, it was found that a crystalline optically activeanhydroecgonine carboxylic acid ester derivative can be obtained byreducing and then dehydrating the optically activetropinonemono-carboxylic acid ester derivative and that its opticalpurity can easily be increased by recrystallization. It was revealedthat such an optically active tropinonemono-carboxylic acid esterderivative obtained according to the present invention is useful as anintermediate for synthesis of 2β-carbomethoxy-3-β-phenyltropane,2-β-carbomethoxy-3-β-(4-iodophenyl)-tropane,2-β-carbomethoxy-3-β-(4-iodophenyl)-8-(3-fluoropropyl)nortropane andtropane alkaloids such as (−)-ferruginine, (+)-knightinol, etc.

1. A process for producing an optically active tropinonemonocarboxylicacid ester derivative which comprises subjecting a tropinonedicarboxylicacid ester derivative represented by the following formula (1):

wherein R′ is an alkyl group, an aralkyl group or an amino-protectinggroup selected from lower aliphatic acyl groups, aromatic acyl groups,lower alkoxycarbonyl groups, aralkyloxycarbonyl groups, aryloxycarbonylgroups and tri-lower-alkylsilyl groups, and R is an alkyl group or anaralkyl group, to asymmetric dealkoxycarbonylation in the presence of anenzyme to obtain an optically active tropinonemonocarboxylic acid esterderivative represented by the following formula (2):

wherein R and R′ are as defined above.
 2. A process for producing anoptically active tropinonemonocarboxylic acid ester derivative accordingto claim 1, wherein the enzyme is liver esterase or baker's yeast.
 3. Aprocess for producing an optically active tropinonemonocarboxylic acidester derivative according to claim 1 or 2, wherein R is an alkyl groupof 1 to 6 carbon atoms and R′ is an aralkyl group, a lower aliphaticacyl group, an aromatic acyl group, an aryloxycarbonyl group or atri-lower-alkylsilyl group; or R is an alkyl group of 2 to 6 carbonatoms and R′ is an aralkyloxycarbonyl group; or each of R and R′ is anaralkyl group.
 4. A process for producing an optically activetropinonemonocarboxylic acid ester derivative according to any one ofclaims 1 to 3, wherein R is an alkyl group of 1 to 6 carbon atomsselected from methyl group, ethyl group, propyl group, isopropyl group,butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group,isopentyl group, neopentyl group, t-pentyl group and hexyl group, and R′is an aralkyl group of 7 to 10 carbon atoms selected from benzyl group,phenethyl group, phenylpropyl group and phenylbutyl group; or R is analkyl group of 2 to 6 carbon atoms selected from ethyl group, propylgroup, isopropyl group, butyl group, isobutyl group, s-butyl group,t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentylgroup and hexyl group, and R′ is an aralkyloxycarbonyl group of 8 or 9carbon atoms selected from benzyloxycarbonyl group andmethoxybenzyloxycarbonyl group; or each of R and R′ is an aralkyl groupof 7 to 10 carbon atoms selected from benzyl group, phenethyl group,phenylpropyl group and phenylbutyl group.
 5. A process for producing anoptically active tropinonemonocarboxylic acid ester derivative whichcomprises reacting succindialdehyde represented by the following formula(3):

with an organic amine represented by the following formula (4):R″—NH₂  (4) wherein R″ is an alkyl group or an aralkyl group, and anacetonedicarboxylic acid ester represented by the following formula (5):

wherein R is an alkyl group or an aralkyl group; if necessary,converting the substituent derived from the substituent R″ of theorganic amine of the formula (4) to an amino-protecting group; therebyobtaining a tropinonedicarboxylic acid ester derivative represented bythe following formula (1):

wherein R′ is an alkyl group, an aralkyl group or an amino-protectinggroup selected from lower aliphatic acyl groups, aromatic acyl groups,lower alkoxycarbonyl groups, aralkyloxycarbonyl groups, aryloxycarbonylgroups and tri-lower-alkylsilyl groups, and R is an alkyl group or anaralkyl group; and then subjecting the tropinonedicarboxylic acid esterderivative to asymmetric dealkoxycarbonylation in the presence of anenzyme to obtain an optically active tropinonemonocarboxylic acid esterderivative represented by the following formula (2):

wherein R and R′ are as defined above.
 6. A process for producing anoptically active tropinonemonocarboxylic acid ester derivative accordingto claim 5, wherein the enzyme is liver esterase or baker's yeast.
 7. Aprocess for producing an optically active tropinonemonocarboxylic acidester derivative according to claim 5 or 6, wherein in the above formula(1), R is an alkyl group of 1 to 6 carbon atoms and R′ is an aralkylgroup, a lower aliphatic acyl group, an aromatic acyl group, anaryloxycarbonyl group or a tri-lower-alkylsilyl group; or R is an alkylgroup of 2 to 6 carbon atoms and R′ is an aralkyloxycarbonyl group; oreach of R and R′ is an aralkyl group.
 8. A process for producing anoptically active tropinonemonocarboxylic acid ester derivative accordingto any one of claims 5 to 7, wherein R is an alkyl group of 1 to 6carbon atoms selected from methyl group, ethyl group, propyl group,isopropyl group, butyl group, isobutyl group, s-butyl group, t-butylgroup, pentyl group, isopentyl group, neopentyl group, t-pentyl groupand hexyl group, and R′ is an aralkyl group of 7 to 10 carbon atomsselected from benzyl group, phenethyl group, phenylpropyl group andphenylbutyl group; or R is an alkyl group of 2 to 6 carbon atomsselected from ethyl group, propyl group, isopropyl group, butyl group,isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentylgroup, neopentyl group, t-pentyl group and hexyl group, and R′ is anaralkyloxycarbonyl group of 8 or 9 carbon atoms selected frombenzyloxycarbonyl group and methoxybenzyloxycarbonyl group; or each of Rand R′ is an aralkyl group of 7 to 10 carbon atoms selected from benzylgroup, phenethyl group, phenylpropyl group and phenylbutyl group.
 9. Aprocess for producing an optically active anhydroecgonine carboxylicacid ester derivative which comprises converting the substituent R′and/or substituent R of the optically active tropinonemonocarboxylicacid ester derivative of the above formula (2) to another substituent orother substituents if necessary, reducing the oxo group at the3-position of this derivative, and then dehydrating the resultingcompound to obtain an optically active anhydroecgonine carboxylic acidester derivative represented by the following formula (6):

wherein R and R′ are as defined above.
 10. A process for producing anoptically active anhydroecgonine carboxylic acid ester derivativeaccording to claim 9, wherein a crystalline optically activeanhydroecgonine carboxylic acid ester derivative is obtained by thereduction and the dehydration, and the obtained crystalline opticallyactive anhydroecgonine carboxylic acid ester derivative is purified byrecrystallization to obtain the anhydroecgonine carboxylic acid esterderivative having a high optical activity.
 11. A process for producingan optically active anhydroecgonine carboxylic acid ester derivativeaccording to claim 9 or 10, wherein the optically activetropinonemonocarboxylic acid ester derivative of the above formula (2)is methyl(1R,5S)-8-t-butoxycarbonyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate,and the obtained optically active anhydroecgonine carboxylic acid esterderivative of the above formula (6) is methyl(1R,5S)-8-t-butoxycarbonyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate.